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1.
Nat Commun ; 11(1): 4929, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004789

RESUMO

Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier's cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.


Assuntos
Barreira Hematoencefálica/metabolismo , Encefalopatias/tratamento farmacológico , Portadores de Fármacos/efeitos da radiação , Agonistas de Receptores de GABA-A/administração & dosagem , Ultrassonografia de Intervenção/métodos , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/efeitos da radiação , Relação Dose-Resposta à Radiação , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Feminino , Agonistas de Receptores de GABA-A/farmacocinética , Humanos , Imagem por Ressonância Magnética , Modelos Animais , Muscimol/administração & dosagem , Muscimol/farmacocinética , Ratos , Técnicas Estereotáxicas , Ondas Ultrassônicas
2.
Carbohydr Polym ; 250: 116800, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33049807

RESUMO

Chitosan, as a biodegradable and biocompatible polymer, is characterized by anti-microbial and anti-cancer properties. It lately has received a widespread interest for use as the pulmonary particulate backbone materials of drug carrier for the treatment of infectious disease and cancer. The success of chitosan as pulmonary particulate drug carrier is a critical interplay of their mucoadhesive, permeation enhancement and site/cell-specific attributes. In the case of nanocarriers, various microencapsulation and micro-nano blending systems have been devised to equip them with an appropriate aerodynamic character to enable efficient pulmonary aerosolization and inhalation. The late COVID-19 infection is met with acute respiratory distress syndrome and cancer. Chitosan and its derivatives are found useful in combating HCoV and cancer as a function of their molecular weight, substituent type and its degree of substitution. The interest in chitosan is expected to rise in the next decade from the perspectives of drug delivery in combination with its therapeutic performance.


Assuntos
Anti-Infecciosos/química , Antineoplásicos/química , Quitosana/análogos & derivados , Portadores de Fármacos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Betacoronavirus/isolamento & purificação , Materiais Biocompatíveis/química , Sobrevivência Celular/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Neoplasias Pulmonares/patologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia
3.
Nat Commun ; 11(1): 4450, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895379

RESUMO

Hollow multishelled structures (HoMSs), with relatively isolated cavities and hierarchal pores in the shells, are structurally similar to cells. Functionally inspired by the different transmission forms in living cells, we studied the mass transport process in HoMSs in detail. In the present work, after introducing the antibacterial agent methylisothiazolinone (MIT) as model molecules into HoMSs, we discover three sequential release stages, i.e., burst release, sustained release and stimulus-responsive release, in one system. The triple-shelled structure can provide a long sterility period in a bacteria-rich environment that is nearly 8 times longer than that of the pure antimicrobial agent under the same conditions. More importantly, the HoMS system provides a smart responsive release mechanism that can be triggered by environmental changes. All these advantages could be attributed to chemical diffusion- and physical barrier-driven temporally-spatially ordered drug release, providing a route for the design of intelligent nanomaterials.


Assuntos
Antibacterianos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/química , Nanoestruturas/química , Antibacterianos/farmacocinética , Preparações de Ação Retardada/farmacocinética , Difusão , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microesferas , Tiazóis/administração & dosagem , Tiazóis/farmacocinética
4.
Nat Commun ; 11(1): 4530, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913195

RESUMO

Various cancer cells have been demonstrated to have the capacity to form plasmonic gold nanoparticles when chloroauric acid is introduced to their cellular microenvironment. But their biomedical applications are limited, particularly considering the millimolar concentrations and longer incubation period of ionic gold. Here, we describe a simplistic method of intracellular biomineralization to produce plasmonic gold nanoparticles at micromolar concentrations within 30 min of application utilizing polyethylene glycol as delivery vector for ionic gold. We have characterized this process for intracellular gold nanoparticle formation, which progressively accumulates proteins as the ionic gold clusters migrate to the nucleus. This nano-vectorized application of ionic gold emphasizes its potential biomedical opportunities while reducing the quantity of ionic gold and required incubation time. To demonstrate its biomedical potential, we further induce in-situ biosynthesis of gold nanoparticles within MCF7 tumor mouse xenografts which is followed by its photothermal remediation.


Assuntos
Cloretos/administração & dosagem , Portadores de Fármacos/química , Compostos de Ouro/administração & dosagem , Ouro/química , Nanopartículas Metálicas/química , Neoplasias/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Animais , Biomineralização/efeitos da radiação , Feminino , Ouro/efeitos da radiação , Humanos , Hipertermia Induzida/métodos , Íons , Células MCF-7 , Nanopartículas Metálicas/efeitos da radiação , Camundongos , Fotoquimioterapia/métodos , Polietilenoglicóis/química , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Int J Nanomedicine ; 15: 6311-6324, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922003

RESUMO

Background: Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) and its over expression in tumor tissues contributes to the increase of interstitial fluid pressure (IFP) and hinders the penetration of nanoparticles into solid tumors. Materials and Methods: We here reported a tumoral microenvironment responsive multistage drug delivery system (NPs-EPI/HAase) which was formed layer by layer via electrostatic interaction with epirubicin (EPI)-loaded PEG-b-poly(2-(diisopropylamino)ethyl methacrylate)-b-poly(2-guanidinoethylmethacrylate) (mPEG-PDPA-PG, PEDG) micelles (NPs-EPI) and hyaluronidase (HAase). In this paper, we focused on the hyaluronidase-combined nanoparticles (NPs-EPI/HAase) for tumor penetration in tumor spheroid and solid tumor models in vitro and in vivo. Results: Our results showed that NPs-EPI/HAase effectively degrade the HA in ECM and facilitate deep penetration of NPs-EPI into solid tumor. Moreover, NPs-EPI mainly employed clathrin-mediated and macropinocytosis-mediated endocytic pathways for cellular uptake and were subsequently directed to the lysosomes for further drug release triggered by proton sponge effect. Compared with NPs-EPI, the HAase coating group showed an enhanced tumoral drug delivery efficacy and inhibition of tumor growth. Conclusion: Overall, our studies demonstrated that coating nanoparticles with HAase can provide a simple but efficient strategy for nano-drug carriers to enhance solid tumor penetration and chemotherapeutic efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Hialuronoglucosaminidase/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Endocitose/efeitos dos fármacos , Epirubicina/farmacologia , Epirubicina/uso terapêutico , Humanos , Antígeno Ki-67/metabolismo , Masculino , Camundongos Nus , Nanopartículas/administração & dosagem , Neoplasias/patologia , Polímeros/química , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
6.
Int J Nanomedicine ; 15: 6385-6399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922007

RESUMO

Purpose: The mononuclear phagocyte system (MPS) presents a formidable obstacle that hampers the delivery of various nanopreparations to tumors. Therefore, there is an urgent need to improve the off-MPS targeting ability of nanomedicines. In the present study, we present a novel preconditioning strategy to substantially increase the circulation times and tumor targeting of nanoparticles by regulating nanocarrier-MPS interactions. Methods: In vitro, the effect of different vacuolar H+-ATPase inhibitors on macrophage uptake of targeted or nontargeted lipid vesicles was evaluated. Specifically, the clinically approved proton-pump inhibitor esomeprazole (ESO) was selected as a preconditioning agent. Then, we further investigated the blocking effect of ESO on the macrophage endocytosis of nanocarriers. In vivo, ESO was first intravenously administered into A549-tumor-bearing nude mice, and 24 h later, the c(RGDm7)-modified vesicles co-loaded with doxorubicin and gefitinib were intravenously injected. Results: In vitro, ESO was found to reduce the interactions between macrophages and c(RGDm7)-modified vesicles by interfering with the latter's lysosomal trafficking. Studies conducted in vivo confirmed that ESO pretreatment greatly decreased the liver and spleen distribution of the targeted vesicles, enhanced their tumor accumulation, and improved the therapeutic outcome of the drug-loaded nanomedicines. Conclusion: Our findings indicate that ESO can regulate the nanoparticle-MPS interaction, which provides a feasible option for enhancing the off-MPS targeting of nanomedicines.


Assuntos
Portadores de Fármacos/química , Esomeprazol/farmacologia , Sistema Fagocitário Mononuclear/citologia , Nanopartículas/química , Células A549 , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transporte Biológico , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Endocitose , Esomeprazol/farmacocinética , Esomeprazol/uso terapêutico , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Células RAW 264.7 , Distribuição Tecidual/efeitos dos fármacos , ATPases Vacuolares Próton-Translocadoras/metabolismo
7.
Int J Nanomedicine ; 15: 6409-6420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922008

RESUMO

Aim: Tumor cell-derived microparticles (MP) can function as a targeted delivery carrier for anti-tumor drugs. Here, we aimed to generate paclitaxel-loaded microparticles (MP-PTX) from HeLa cells and examined its therapeutic potential on human cervical carcinoma. Methods: MP-PTX was generated from HeLa cells by ultraviolet radiation and subsequent centrifugation. The particle size, drug loading rate, and stability of MP-PTX were examined in vitro. Flow cytometry and the MTT assay were performed to test the inhibitory effect of MP-PTX using different cell lines. Immunodeficient mice bearing HeLa cervical carcinoma were treated with 0.9% normal saline, MP, paclitaxel (PTX) (2.5 mg/kg), or MP-PTX (PTX content identical to PTX group) every day for 6 consecutive days. Tumor volume and animal survival were observed. Micro 18F-FDG PET/CT was performed to monitor the therapeutic efficacy. The proliferation activity of cells and microvessel density in tumor tissues were determined by immunohistochemical staining using Ki-67 and CD31, respectively. Results: Dynamic laser scattering measurements showed that the particle size of MP-PTX was 285.58 ± 2.95 nm and the polydispersity index was 0.104 ± 0.106. And the particle size of MP-PTX was not change at 4°C for at least one week. More than 1% of PTX in the medium could be successfully encapsulated into HeLa cell-derived MP. When compared with PTX, MP-PTX treatment significantly increased apoptosis of tumor cells and reduced their proliferation. In addition, MP-PTX showed lower toxicity to normal human umbilical vein endothelial cells (HUVEC) than PTX. In vivo studies further demonstrated that MP-PTX treatment significantly inhibited the growth of cervical carcinoma, prolonged the survival of tumor-bearing mice, and reduced the toxicity of PTX. Immunohistochemical staining revealed that MP-PTX treatment led to decreased Ki-67 positive tumor cells and decreased microvessel density in tumor tissues. Conclusion: Our results demonstrated that HeLa-derived MP-PTX significantly enhanced the anti-cancer effects of PTX with reduced toxicity, which may provide a novel strategy for the treatment of cervical carcinoma.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Paclitaxel/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Micropartículas Derivadas de Células/efeitos dos fármacos , Portadores de Fármacos/química , Células Endoteliais/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Fisiológica/efeitos dos fármacos , Paclitaxel/farmacologia , Tamanho da Partícula
8.
Int J Nanomedicine ; 15: 6485-6502, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922012

RESUMO

Extracellular vesicles (EVs) are a class of cell-derived, lipid bilayer membrane composed vesicles, and some of them such as exosomes and ectosomes have been proven, playing remarkable roles in transmitting intercellular information, and being involved in each property of cell physiological activities. Nowadays, EVs are considered as potential nanocarriers which could partially resolve the problems of current chemotherapy because of their distinctive advantages. As endogenous membrane encompassed vesicles with nanosize, EVs are able to pass through the natural barriers with prolonged circulation time in vivo and have intrinsic cell targeting properties, they are less toxic, and less immunogenic. Recently, studies focusing on EV-based drug delivery system for cancer therapy have exploded dramatically. This review aims to outline the current applications of EVs as potential nanosized drug carriers in cancer therapy. Firstly, the characteristics and biofunctions of each EV subtype are described. Then the variety of therapeutic cargoes, the loading methods, and the targeting strategy of engineered EVs are emphatically introduced. Thereafter the pros and cons of EVs applied as therapeutic carriers, as well as the future prospects in this field, are discussed.


Assuntos
Portadores de Fármacos/química , Vesículas Extracelulares/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos
9.
J Med Life ; 13(2): 195-199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32742513

RESUMO

Polyurethane nano- and micro-structures have been studied intensively in the last decade as drug delivery systems for various herbal extracts as well as pure active biological substances. Their biocompatibility, haemocompatibility, safe degradation, and low-cost production are just a few advantages of these materials that were already used in numerous medical applications (catheters, surgical drapes, wound dressing). The primary purposes of this study include obtaining empty polyurethane microstructures and the assessment of their modifications in media with different pH values. A mixture of two aliphatic diisocyanates and an aqueous phase based on a polyether were used during the synthesis process. The size, homogeneity, and surface charge were studied using a Cordouan Technol. Zetasizer, while the pH measurements were conducted with a portable pH Meter Checker®, Hanna Instruments. The results showed the obtaining of an almost homogeneous sample containing microstructures with sizes ranging between 139 and 151 nm, with a pH value of approximately 6.78 and a Zeta potential of 24.6. Expected decreases in microparticles' sizes were observed in all types of media during a 15-days experiment, but the process was accelerated by a low pH when an increase of the Zeta potential value was noticed as well. Our data provide new information about the degradation process of the polyurethane microstructures on the one hand and the drug release rate of these materials when used as drug carriers, on the other hand.


Assuntos
Portadores de Fármacos/química , Poliuretanos/química , Concentração de Íons de Hidrogênio , Tamanho da Partícula , Eletricidade Estática
10.
Ther Deliv ; 11(8): 521-534, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32757745

RESUMO

Nanoscale size-dependent properties give nanomaterials unique specifications that are robust in many applications of human medicine. Gold nanoparticles (AuNPs) have recently gained attention because of their unique optical, physical and electrical properties. AuNPs increase the efficacy of biomedical applications in diagnostic treatments for infectious diseases, by targeting or labeling target cells/bioactive compounds. However, it is imperative to develop the regimens for more accurate diagnostic tools, preventive care and effective therapy. Our critical and comprehensive review presents emerging avenues of molecular diagnostics as well as therapeutics translated into clinical approaches. This manuscript critically reviews the rampant future of AuNPs in the diagnosis and treatment of the most important diseases, such as cancer and viruses of respiratory system.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Portadores de Fármacos/química , Humanos , Pneumopatias/diagnóstico , Pneumopatias/terapia , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Pandemias , Fototerapia , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Pneumonia Viral/virologia
11.
Crit Rev Ther Drug Carrier Syst ; 37(3): 205-227, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749138

RESUMO

In this review, we describe the advances in oral drug delivery approaches for taxanes for successful therapeutic outcome. Taxanes (paclitaxel and docetaxel) have unwanted pharmacokinetic profiles when they are given in their current dosage forms. Taxanes have low bioavailability, are extensively metabolized by CYP3A, and have a high affinity for P-glycoprotein. Regardless of dosage schedule, the overall docetaxel or paclitaxel dose that a patient can tolerate at a given interval remains similar. Currently, there are no commercially available oral taxane nanoformulations, and there are still several challenges to overcome. Nano-based formulations may offer the best solutions to problems involving the safety and effectiveness of taxane delivery. Thus, further research is necessary before such taxane nanoformulations can be manufactured for clinical use.


Assuntos
Docetaxel/administração & dosagem , Paclitaxel/administração & dosagem , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Ensaios Clínicos como Assunto , Docetaxel/química , Docetaxel/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Humanos , Lipídeos/administração & dosagem , Lipídeos/química , Micelas , Nanopartículas/administração & dosagem , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacocinética
12.
Crit Rev Ther Drug Carrier Syst ; 37(3): 229-269, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749139

RESUMO

Nanostructured drug delivery formulations have lately gained enormous attention, contributing to their systematic development. Issuance of quality by design (QbD) guidelines by ICH, FDA, and other federal agencies, in this regard, has notably influenced the overall development of drug products, enabling holistic product and process understanding. Owing to the applicability of QbD paradigms, a science lately christened as formulation by design (FbD) has been dedicated exclusively to QbD-enabled drug product development. Consisting of the principal elements of design of experiments (DoE), quality risk management (QRM), and QbD-enabled product comprehension as the fundamental tools in the implementation of FbD, a variety of drug nanocargos have been successfully developed with FbD paradigms and reported in the literature. FbD aims to produce novel and advanced systems utilizing nominal resources of development time, work effort, and money. A systematic FbD approach envisions the entire developmental path through pivotal milestones of risk assessment, factor screening and optimization (both using appropriate experimental designs), multivariate statistical and optimum search tools, along with response surface modeling, usually employing suitable computer software. The design space is one of the fundamental elements of FbD providing the most sought-after regulatory flexibility to pharma companies, postapproval. The present paper provides a bird's eye view of the fundamental aspects of FbD terminology, methodology, and applications in the development of a wide range of nanocargos, as well as a discussion of trends from both technological and regulatory perspectives.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Nanoestruturas/química , Portadores de Fármacos/administração & dosagem , Composição de Medicamentos , Humanos , Nanoestruturas/administração & dosagem , Controle de Qualidade
13.
Int J Nanomedicine ; 15: 4763-4778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753865

RESUMO

Introduction: Methotrexate exhibits poor cutaneous bioavailability and systemic side effects on topical administration, so there is an unmet need for a novel carrier and its optimized therapy. Methotrexate-loaded nanostructured lipid carriers (MTXNLCs) were formulated and characterized to determine in vitro drug release and evaluate the role of MTXNLC gel in the topical treatment of psoriasis. Methods: A solvent diffusion technique was employed to prepare MTXNLCs, which was optimized using 32 full factorial designs. The mean diameter and surface morphology of MTXNLCs was evaluated. The crystallinity of lyophilized MTXNLCs was characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). MTXNLCs were integrated in 1% w/w Carbopol 934 P gel base, and in vitro skin deposition studies in human cadaver skin (HCS) were carried out. Results: The optimized MTXNLCs were rod-shaped, with an average particle size of 253 ± 8.65 nm, a zeta potential of -26.4±0.86 mV, and EE of 54.00±1.49%. DSC and XRD data confirmed the formation of NLCs. Significantly higher deposition of MTX was found in HCS from MTXNLC gel (71.52 ±1.13%) as compared to MTX plain gel (38.48±0.96%). In vivo studies demonstrated significant improvement in therapeutic response and reduction in local side effects with MTXNLCs-loaded gel in the topical treatment of psoriasis. Anti-psoriatic efficacy of MTXNLCs 100 ug/cm2 compared with plain MTX gel was evaluated using imiquimod (IMQ)-induced psoriasis in BALB/c mice. The topical application of MTXNLCs to the mouse ear resulted in a significant reduction of psoriatic area and severity index, oxidative stress, inflammatory cytokines like TNF-α, IL-1ß, and IL-6 and IMQ-induced histopathological alterations in mouse ear samples. Conclusion: Developed formulation of MTXNLC gel demonstrated better anti-psoriatic activity and also displayed prolonged and sustained release effect, which shows that it can be a promising alternative to existing MTX formulation for the treatment of psoriasis.


Assuntos
Composição de Medicamentos , Géis/química , Imiquimode/uso terapêutico , Inflamação/tratamento farmacológico , Lipídeos/química , Metotrexato/uso terapêutico , Nanoestruturas/química , Psoríase/tratamento farmacológico , Administração Cutânea , Administração Tópica , Animais , Catalase/metabolismo , Citocinas/metabolismo , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Glutationa/metabolismo , Humanos , Inflamação/patologia , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , Nanoestruturas/ultraestrutura , Tamanho do Órgão , Superóxido Dismutase/metabolismo
14.
Chem Biol Interact ; 329: 109221, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32768398

RESUMO

Cancer continues to be one of the most challenging diseases to be treated and is one of the leading causes of deaths around the globe. Cancers account for 13% of all deaths each year, with cancer-related mortality expected to rise to 13.1 million by the year 2030. Although, we now have a large library of chemotherapeutic agents, the problem of non-selectivity remains the biggest drawback, as these substances are toxic not only to cancerous cells, but also to other healthy cells in the body. The limitations with chemotherapy and radiation have led to the discovery and development of novel strategies for safe and effective treatment strategies to manage the menace of cancer. Researchers have long justified and have shed light on the emergence of nanotechnology as a potential area for cancer therapy and diagnostics, whereby, nanomaterials are used primarily as nanocarriers or as delivery agents for anticancer drugs due to their tumor targeting properties. Furthermore, nanocarriers loaded with chemotherapeutic agents also overcome biological barriers such as renal and hepatic clearances, thus improving therapeutic efficacy with lowered morbidity. Theranostics, which is the combination of rationally designed nanomaterials with cancer-targeting moieties, along with protective polymers and imaging agents has become one of the core keywords in cancer research. In this review, we have highlighted the potential of various nanomaterials for their application in cancer therapy and imaging, including their current state and clinical prospects. Theranostics has successfully paved a path to a new era of drug design and development, in which nanomaterials and imaging contribute to a large variety of cancer therapies and provide a promising future in the effective management of various cancers. However, in order to meet the therapeutic needs, theranostic nanomaterials must be designed in such a way, that take into account the pharmacokinetic and pharmacodynamics properties of the drug for the development of effective carcinogenic therapy.


Assuntos
Antineoplásicos/uso terapêutico , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Nanomedicina Teranóstica , Antineoplásicos/química , Portadores de Fármacos/química , Desenho de Fármacos , Humanos , Neoplasias/patologia , Microambiente Tumoral
15.
Nat Protoc ; 15(9): 3064-3087, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32807907

RESUMO

Targeted downregulation of select endogenous plant genes is known to confer disease or pest resistance in crops and is routinely accomplished via transgenic modification of plants for constitutive gene silencing. An attractive alternative to the use of transgenics or pesticides in agriculture is the use of a 'green' alternative known as RNAi, which involves the delivery of siRNAs that downregulate endogenous genes to confer resistance. However, siRNA is a molecule that is highly susceptible to enzymatic degradation and is difficult to deliver across the lignin-rich and multi-layered plant cell wall that poses the dominant physical barrier to biomolecule delivery in plants. We have demonstrated that DNA nanostructures can be utilized as a cargo carrier for direct siRNA delivery and gene silencing in mature plants. The size, shape, compactness and stiffness of the DNA nanostructure affect both internalization into plant cells and subsequent gene silencing efficiency. Herein, we provide a detailed protocol that can be readily adopted with standard biology benchtop equipment to generate geometrically optimized DNA nanostructures for transgene-free and force-independent siRNA delivery and gene silencing in mature plants. We further discuss how such DNA nanostructures can be rationally designed to efficiently enter plant cells and deliver cargoes to mature plants, and provide guidance for DNA nanostructure characterization, storage and use. The protocol described herein can be completed in 4 d.


Assuntos
DNA/química , Portadores de Fármacos/química , Engenharia , Nanoestruturas/química , RNA Interferente Pequeno/metabolismo , Tabaco/metabolismo , DNA/metabolismo , Portadores de Fármacos/metabolismo , RNA Interferente Pequeno/genética , Tabaco/genética
16.
Int J Nanomedicine ; 15: 5181-5202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801685

RESUMO

Background: Combating infectious diseases caused by influenza virus is a major challenge due to its resistance to available drugs and vaccines, side effects, and cost of treatment. Nanomedicines are being developed to allow targeted delivery of drugs to attack specific cells or viruses. Materials and Methods: In this study, mesoporous silica nanoparticles (MSNs) functionalized with amino groups and loaded with natural prodrugs of shikimic acid (SH), quercetin (QR) or both were explored as a novel antiviral nanoformulations targeting the highly pathogenic avian influenza H5N1 virus. Also, the immunomodulatory effects were investigated in vitro tests and anti-inflammatory activity was determined in vivo using the acute carrageenan-induced paw edema rat model. Results: Prodrugs alone or the MSNs displayed weaker antiviral effects as evidenced by virus titers and plaque formation compared to nanoformulations. The MSNs-NH2-SH and MSNs-NH2-SH-QR2 nanoformulations displayed a strong virucidal by inactivating the H5N1 virus. They induced also strong immunomodulatory effects: they inhibited cytokines (TNF-α, IL-1ß) and nitric oxide production by approximately 50% for MSNs-NH2-SH-QR2 (containing both SH and QR). Remarkable anti-inflammatory effects were observed during in vivo tests in an acute carrageenan-induced rat model. Conclusion: Our preliminary findings show the potential of nanotechnology for the application of natural prodrug substances to produce a novel safe, effective, and affordable antiviral drug.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antivirais/farmacologia , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Nanopartículas/química , Pró-Fármacos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/imunologia , Antivirais/imunologia , Citocinas/metabolismo , Cães , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Edema/tratamento farmacológico , Edema/metabolismo , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacologia , Células Madin Darby de Rim Canino , Masculino , Camundongos , Quercetina/imunologia , Quercetina/farmacologia , Ratos , Ácido Chiquímico/imunologia , Ácido Chiquímico/farmacologia , Dióxido de Silício/química
17.
Int J Nanomedicine ; 15: 5253-5264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801690

RESUMO

Background and Aim: Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery. Methods: Box-Behnken design was applied to explore the impact of solid lipid % (SL%, X 1), liquid lipid % (LL%, X 2), and sonication time (ST, X 3) on particle size. The optimized NLC formulation was characterized and incorporated into gellan gum in situ gel. The prepared gel was subjected to in vitro drug release, in vivo pharmacokinetic performance, and histopathological assessment in rats. Results: Statistical analysis revealed a significant negative effect for both SL% and ST on NLCs size. In contrast, a significant positive effect was observed for the LL%. The optimized formulation showed spherical shape with vesicular size of 114.63 nm. The optimized FLB-NLC in situ gel exhibited adequate stability and enhanced in vitro release compared to raw FLB control gel. The plasma and brain concentrations of the drug after nasal administration in rats increased by more than 3-6-fold, respectively, compared to raw FLB in situ gel. In addition, the histopathological studies revealed the absence of any pathological signs. Conclusion: The aforementioned results highlight the safety of FLB-NLC in situ nasal gel and its potential to improve the drug bioavailability and brain delivery.


Assuntos
Benzimidazóis/administração & dosagem , Encéfalo/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Nanoestruturas/administração & dosagem , Administração Intranasal , Animais , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Géis , Lipídeos/administração & dosagem , Lipídeos/química , Masculino , Nanoestruturas/química , Tamanho da Partícula , Polissacarídeos Bacterianos/química , Ratos Wistar , Solubilidade
18.
Int J Nanomedicine ; 15: 5333-5344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801692

RESUMO

Purpose: Cabazitaxel (CBZ) is a new taxane-based antitumor drug approved by the FDA for the treatment of prostate cancer, especially for patients with advanced prostate cancer for whom docetaxel is ineffective or causes aggravation. However, Tween 80 injection can cause serious allergic reactions, and CBZ itself has strong toxicity, adverse reactions, and poor tumor selectivity, which greatly limits its clinical applications. Therefore, the CBZ-loaded bovine serum albumin nanoparticles (CBZ-BSA-Gd-NPs) were developed to overcome the allergenic response of Tween 80 and realize the integration of diagnosis and treatment. Methods: CBZ-BSA-Gd-NPs were prepared by the biomineralization method. The characterization, magnetic resonance imaging (MRI), safety, and antitumor activity of the nanoparticles were evaluated in vitro and in vivo. Results: The prepared nanoparticles were uniform in size (166 nm), with good MRI performance and stability over 24 h. Compared with CBZ-Tween 80 injection, CBZ-BSA-Gd-NPs showed much lower hemolysis, similar tumor inhibition, and enhanced cellular uptake in vitro. The pharmacokinetic behavior of CBZ-BSA-Gd-NPs in rats showed that the retention time of the nanoparticles was prolonged, the clearance rate decreased, and the area under the drug-time curve increased. The distribution of CBZ-BSA-Gd-NPs in nude mice was characterized by UPLC-MS/MS and MRI, and the results showed that CBZ-BSA-Gd-NPs could effectively target tumor tissues with reduced distribution in the heart, liver, spleen, lungs, and kidneys compared with CBZ-Tween 80, which indicated that CBZ-BSA-Gd-NPs not only had a passive targeting effect on tumor tissue but also achieved the integration of diagnosis and treatment. In vivo, CBZ-BSA-Gd-NPs showed improved tumor inhibitory effect with a safer profile. Conclusion: In summary, CBZ-BSA-Gd-NPs can serve as an effective therapeutic drug carrier to deliver CBZ into prostate cancer, and realize the integration of diagnosis and therapy.


Assuntos
Antineoplásicos/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Soroalbumina Bovina/administração & dosagem , Taxoides/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cromatografia Líquida , Meios de Contraste/administração & dosagem , Meios de Contraste/farmacocinética , Docetaxel , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Neoplasias da Próstata/diagnóstico por imagem , Ratos Sprague-Dawley , Soroalbumina Bovina/farmacocinética , Espectrometria de Massas em Tandem , Taxoides/farmacocinética , Distribuição Tecidual
19.
Int J Nanomedicine ; 15: 3851-3868, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764919

RESUMO

Purpose: The aim of this study was to develop a means of improving the bioavailability and anticancer activity of urushiol by developing an urushiol-loaded novel tumor-targeted micelle delivery system based on amphiphilic block copolymer poly(ethylene glycol)-b-poly-(ß-amino ester) (mPEG-PBAE). Materials and Methods: We synthesized four different mPEG-PBAE copolymers using mPEG-NH2 with different molecular weights or hydrophobicity levels. Of these, we selected the mPEG5000-PBAE-C12 polymer and used it to develop an optimized means of preparing urushiol-loaded micelles. Response surface methodology was used to optimize this formulation process. The micellar properties, including particle size, pH sensitivity, drug release dynamics, and critical micelle concentrations, were characterized. We further used the MCF-7 human breast cancer cell line to explore the cytotoxicity of these micelles in vitro and assessed their pharmacokinetics, tissue distribution, and antitumor activity in vivo. Results: The resulting micelles had a mean particle size of 160.1 nm, a DL value of 23.45%, and an EE value of 80.68%. These micelles were found to release their contents in a pH-sensitive manner in vitro, with drug release being significantly accelerated at pH 5.0 (98.74% in 72 h) without any associated burst release. We found that urushiol-loaded micelles were significantly better at inducing MCF-7 cell cytotoxicity compared with free urushiol, with an IC50 of 1.21 mg/L. When these micelles were administered to tumor model animals in vivo, pharmacokinetic analysis revealed that the total AUC and MRT of these micelles were 2.28- and 2.53-fold higher than that of free urushiol, respectively. Tissue distribution analyses further revealed these micelles to mediate significantly enhanced tumor urushiol accumulation. Conclusion: The pH-responsive urushiol-loaded micelles described in this study may be ideally suited for clinical use for the treatment of breast cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Catecóis/química , Catecóis/farmacologia , Micelas , Polietilenoglicóis/química , Polímeros/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Catecóis/farmacocinética , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Tamanho da Partícula , Distribuição Tecidual
20.
Int J Nanomedicine ; 15: 4793-4810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764921

RESUMO

Background: Platinum resistance is a major challenge in the management of ovarian cancer. Even low levels of acquired resistance at the cellular level lead to impaired response to cisplatin. In ovarian cancer intraperitoneal therapy, nanoparticle formulation can improve the cisplatin's pharmacokinetics and safety profile. Purpose: This work aimed to investigate the chemo-sensitivity of ovarian cancer SKOV3 cells upon short-term (72h) single treatment of cisplatin and cisplatin-loaded biodegradable nanoparticles (Cis-NP). The aim was then to determine the therapeutic properties of Cis-NP in vivo using a SKOV3-luc cells' xenograft model in mice. Methods: Cell cytotoxicity was assessed after the exposure of the cell culture to cisplatin or Cis-NP. The effect of treatments on EMT and CSC-like phenotype was studied by analyzing a panel of markers by flow cytometry. Intracellular platinum concentration was determined by inductively coupled plasma mass spectrometry (ICS-MS), and gene expression was evaluated by RNAseq analysis. The efficacy of intraperitoneal chemotherapy was evaluated in a SKOV3-luc cells' xenograft model in mice, through a combination of bioluminescence imaging, histological, and immunohistochemical analyses. Results: We observed in vitro that short-term treatment of cisplatin has a critical role in determining the potential induction of chemoresistance, and a nanotechnology-based drug delivery system can modulate it. The RNAseq analysis underlines a protective effect of nanoparticle system according to their ability to down-regulate several genes involved in chemoresistance, cell proliferation, and apoptosis. The highest intracellular platinum concentration obtained with Cis-NP treatment significantly improved the efficacy. Consistent with in vitro results, we found that Cis-NP treatment in vivo can significantly reduce tumor burden and aggressiveness compared to the free drug. Conclusion: Nanoparticle-mediated cisplatin delivery may serve as an intracellular depot impacting the cisplatin pharmacodynamic performance at cellular levels. These features may contribute to improving the drawbacks of conventional intraperitoneal therapy, and therefore will require further investigations in vivo.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Portadores de Fármacos/química , Espaço Intracelular/metabolismo , Nanomedicina/métodos , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/metabolismo , Cisplatino/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
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